Eosinophil-derived IL-13 promotes emphysema.

Abstract

The inflammatory responses in chronic airway diseases leading to emphysema are not fully defined. We hypothesised that lung eosinophilia contributes to airspace enlargement in a mouse model and to emphysema in patients with chronic obstructive pulmonary disease (COPD).A transgenic mouse model of chronic type 2 pulmonary inflammation (I5/hE2) was used to examine eosinophil-dependent mechanisms leading to airspace enlargement. Human sputum samples were collected for translational studies examining eosinophilia and matrix metalloprotease (MMP)-12 levels in patients with chronic airways disease.Airspace enlargement was identified in I5/hE2 mice and was dependent on eosinophils. Examination of I5/hE2 bronchoalveolar lavage identified elevated MMP-12, a mediator of emphysema. We showed, in vitro, that eosinophil-derived interleukin (IL)-13 promoted alveolar macrophage MMP-12 production. Airspace enlargement in I5/hE2 mice was dependent on MMP-12 and eosinophil-derived IL-4/13. Consistent with this, MMP-12 was elevated in patients with sputum eosinophilia and computed tomography evidence of emphysema, and also negatively correlated with forced expiratory volume in 1 s.A mouse model of chronic type 2 pulmonary inflammation exhibited airspace enlargement dependent on MMP-12 and eosinophil-derived IL-4/13. In chronic airways disease patients, lung eosinophilia was associated with elevated MMP-12 levels, which was a predictor of emphysema. These findings suggest an underappreciated mechanism by which eosinophils contribute to the pathologies associated with asthma and COPD.

• Authors: Alfred D Doyle, Manali Mukherjee, William E LeSuer, Tyler B Bittner, Saif M Pasha, Justin J Frere, Joseph L Neely, Jake A Kloeber, Kelly P Shim, Sergei I Ochkur, Terence Ho, Sarah Svenningsen, Benjamin L Wright, Matthew A Rank, James J Lee, Parameswaran Nair, Elizabeth A Jacobsen
• Journal: The European respiratory journal (Eur Respir J) Vol. 53 Issue 5 (05 2019) ISSN: 1399-3003 [Electronic] England
• PMID: 30728205 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright ©ERS 2019.

Chemical References

• Interleukin-13
• Interleukin-4
• MMP12 protein, human
• Matrix Metalloproteinase 12

Topics

• Aged
• Animals
• Asthma (immunology, pathology)
• Disease Models, Animal
• Eosinophils (immunology, pathology)
• Female
• Humans
• Interleukin-13 (immunology)
• Interleukin-4 (immunology)
• Macrophages, Alveolar (pathology)
• Male
• Matrix Metalloproteinase 12 (immunology)
• Mice
• Mice, Transgenic
• Middle Aged
• Multivariate Analysis
• Pneumonia (etiology, immunology, pathology)
• Pulmonary Disease, Chronic Obstructive (diagnosis, immunology, pathology)
• Pulmonary Emphysema (etiology, immunology, pathology)
• Regression Analysis
• Respiratory System (physiopathology)